Synthesis of chalcone analogues with increased antileishmanial activity Paula Boeck, a Camila Alves Bandeira Falca ˜o, c Paulo Ce ´sar Leal, a Rosendo Augusto Yunes, a Valdir Cechinel Filho, b Eduardo Caio Torres-Santos c and Bartira Rossi-Bergmann c, * a Universidade Federal de Santa Catarina, Departamento de Quı ´mica, Campus Trindade, CEP 88.040-90, Floriano ´ polis, SC, Brazil b Nu ´ cleo de Investigac ¸o ˜es Quı ´mico-Farmace ˆuticas (NIQFA/CCS), Universidade do Vale do Itajaı ´, CEP 88.303-202 Itajaı ´, SC, Brazil c Universidade Federal do Rio de Janeiro, Instituto de Biofı ´sica Carlos Chagas Filho, Ilha do Funda ˜o, CEP 21.949-900 Rio de Janeiro, RJ, Brazil Received 10 December 2004; revised 2 August 2005; accepted 4 October 2005 Available online 28 December 2005 Abstract—Eighteen analogues of an active natural chalcone were synthesized using xanthoxyline and some derivatives, and these analogues were tested for selective activity against both promastigotes and intracellular amastigotes of Leishmania amazonensis in vitro. Three analogues (10, 12, and 19) containing nitro, fluorine or bromine groups, respectively, displayed increased selective activity against the parasites as compared with the natural chalcone. The nitrosylated chalcone 10 was also tested intralesionally in infected mice and was found to be as effective as Pentostan reference drug at a dose 100 times higher than that of the chalcone in controlling both the lesion growth and the parasite burden. Ó 2005 Elsevier Ltd. All rights reserved. 1. Introduction Leishmaniases are a group of diseases caused by differ- ent species of the protozoan parasite Leishmania, which affect more than 12 million people worldwide. 1 The clinical manifestations may range from single cutaneous lesions to fatal visceral leishmaniasis. Conventional chemotherapy relies on multiple parenteral injections with pentavalent antimonials that are considerably toxic and prone to induce resistance. Second-line drugs, such as Amphotericin B and its lipid formulations, are either too toxic or expensive for routine use in developing countries. At the same time, the efficacy of Miltefosine against cutaneous leishmaniasis remains to be ascer- tained. 2,3 These facts call for safer, cheaper, and more effective new antileishmanial drugs. In the past decade, chalcones emerged as a new class of antileishmanial agents. 4–7 Chalcones are structurally simple compounds of the flavonoid family and are present in a variety of plant species with a vast spectrum of pharmacological activities including antibacterial, antifungal, immunosuppressive, and antinociceptive properties. 8–10 One of the most studied antileishmanial chalcones is licochalcone A isolated from the Glycyrrhi- za spp. Chinese plant, which inhibits the parasite enzyme fumarate reductase. 11 However, licochalcone A and some synthetic derivatives have also been shown to affect human cell functioning by inhibiting lympho- cyte proliferation and cytokine production. 12 We have previously reported the selective activity of the 2 0 ,6 0 -dihydroxy-4 0 -methoxychalcone (DMC) isolated from the inflorescences of Piper aduncum against intra- cellular amastigotes of Leishmania amazonensis 13 and the improvement of its therapeutic activity in mice by encapsulation in biodegradable nanospheres. 14 Aiming at developing compounds with improved antileishma- nial activity, we synthesized a similar active chalcone (2 0 -hydroxy-4 0 ,6 0 -dimethoxychalcone, compound 2) by using xanthoxyline, a natural compound present in the leaves and stems of Sebastiana chottiana 15 with reported antibacterial, 16 antifungal, 17 and antioedematogenic 18 properties. In this work, other 17 chalcone analogues were then synthesized by base-catalyzed condensation Bioorganic & Medicinal Chemistry 14 (2006) 1538–1545 0968-0896/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved. doi:10.1016/j.bmc.2005.10.005 Keywords: Chalcone; Leishmania; Xanthoxyline; Cutaneous leishmaniasis. * Corresponding author. Tel.: +55 21 2260 6963; fax: +55 21 2280 8193; e-mail: bartira@biof.ufrj.br